The differential protection of functional groups of similar reactivity is a major challenge for the synthesis of complex natural products. The task of distinguishing specific hydroxyl and amino functionalities becomes particularly daunting in carbohydrate chemistry when highly branched structures call for several selectively removable masking groups. Over the years a host of protecting groups has been introduced, each making use of the unique reactivity of the particular masking moiety. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; John Wiley and Sons; New York, 1999. Traditionally, benzyl ethers have been employed for xe2x80x98permanentxe2x80x99 protection and are removed during the late stages of the synthesis, while ester moieties and silyl ethers are used to xe2x80x98temporarilyxe2x80x99 mask hydroxyl groups to be unveiled during the synthesis. Orthogonality of protecting groups, or the ability to remove one particular masking entity without affecting the others, is a key issue for synthetic planning and experimental execution.
The reactivity of benzyl ethers has been tuned by using substituted benzyl ether protecting groups which could be selectively removed in the presence of unsubstituted benzyl ethers. These substituted benzyl ethers were generally less stable to reaction conditions than unsubstituted benzyl ethers. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; John Wiley and Sons; New York, 1999, p 86-113. The 4-O-methoxy benzyl group (PMB) has found frequent applications in natural product synthesis since it can be cleaved oxidatively thus sparing most other protective groups. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; John Wiley and Sons; New York, 1999, p 86-91. The acid sensitivity of this group has somewhat restricted its synthetic utility. More recently, other 4-O-substituted benzyl ethers containing acetate and silyl substituents have been reported. Jobron, L.; Hindsgaul, O. J. Am. Chem. Soc. 1999, 121, 5835-5836. While these benzyl ether groups do not require palladium catalyzed hydrogenation for their removal, they necessitate treatment with base or fluoride respectively, followed by oxidative cleavage. These deprotection protocols forfeit compatibility of these 4-substituted benzyl ethers with ester, silyl, or PMB protecting groups.
One aspect of the present invention relates to optionally substituted halogenated benzyl halides and the like. These compounds are useful as halogenated benzyl ether-based protecting groups for a variety of functional groups, e.g., alcohols, thiols, amines, carboxylic acids, and phosphoric acids. The corresponding protected functional groups are stable to a wide range of reaction conditions; however, they can be removed readily using methods of the present invention.
Certain methods of the present invention pertain to the selective removal of the benzyl ether-based protecting groups of the present invention. These methods comprise the steps of: replacing the halide moiety of the protecting group with a heteroatomic group, e.g., an alcohol, thiol, or amine, via transition metal catalysis to give a second benzyl ether-based protecting group (incorporating said heteroatomic group); and removing said second benzyl ether-based protecting group by treatment with a Lewis acid or oxidizing agent.
Another aspect of the present invention relates to use of the protecting groups and methods in concert to develop and exploit an orthogonal protecting group strategy for the synthesis of complex molecules, e.g., natural products, oligosaccharides, or combinatorial libraries of one or both, comprising a number of functional groups selected from the group comprising alcohols, thiols, amines, carboxylic acids, and phosphoric acids.
Another aspect of the present invention relates to mono- and oligo-saccharides bearing various arrays of protecting groups of the present invention. These compounds will be useful to synthetic, medicinal, and process chemists pursuing the synthesis of oligo- and poly-saccharides and glycoconjugates. Furthermore, another aspect of the present invention relates to a method of synthesizing an oligosaccharide or glycoconjugate, comprising the steps of: using a mono- or oligo-saccharide bearing at least one protecting group of the present invention to glycosylate a molecule to give a product comprising said mono- or oligo-saccharide; and removing at least one protecting group of the present invention from said product.